Summary: Research in the Molecular Pathogenesis Section is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Currently under investigation are the inherited breast and ovarian cancer genes, BRCA1 and BRCA2. These proteins function in the DNA repair pathways. Previously, we discovered which proteins specifically interact with BRCA1. We also have found that BRCA1 is important for controlling the expression of other genes and plays a role in DNA repair. Additional experiments under this project have revealed that BRCA1 appears to help in the process of recognizing and eliminating cells that may progress to form tumors. We now know that the increase in breast, ovarian and prostate cancer risk associated with genetic variants in these genes is due to a failure of these mutated proteins to function in the DNA repair pathway. The lab no longer works on the experimental biology of the BRCA1 and BRCA2 genes. The major effort in the lab in this area is focused on improving and maintaining an important scientific resource, an open access database of mutations in the breast cancer genes, BRCA1 and BRCA2. This scientific resource, called the BIC database (http://research.nhgri.nih.gov/bic/) is used by investigators throughout the world. It remains the most highly accessed intramural research website. A sample of the users of the data include the following: basic scientists, clinical testing labs, individual patients, commercial entities and legal scholars. The database to allows users to assess the clinical and functional significance of mutations. We are collaborating with the ENIGMA Consortium (enigmaconsortium.org) to capture information as to the medical significance of specific mutations. This information is now captured and displayed in the database allowing multiple additional labs to offer BRCA1 and BRCA2 mutation testing. This project contributed to the understanding of the genome. We worked with investigators at the National Center for Biotechnology Information (NCBI) to have the data in the BIC represented in the central genomic databases. This is important as locus specific information was not captured and annotated in earlier displays of human genome. We deposited the entire list of BIC variants into dbGAP. As part of the process, each variant is assigned an rs number. This number serves as a unique identifier for the variant. Over the last two years, we have transitioned away from being a data collection center for BRCA data. We now refer investigators to ClinVar. The group at NCBI has greatly expanded the CLINVAR database. All of the data collected in the BIC database has been duplicated and transferred to NCBI to and integrated into the ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/). The integration of the BIC data into the central genome database at NCBI has had several important practical implications. The most important is that the BIC data is now displayed on the three most important genome browser server/websites. This produces an avenue for global distribution of these data above and beyond the thousands of users who access the BIC data directly at NHGRI. Four years ago, we contributed all of the data contained in the BIC to the prototype of the ClinVar database. User feedback from those looking at BRCA data in ClinVar has identified usability issues with ClinVar. This suggests that there remains a role for the BIC database for the near future. Our plan going forward is to have BIC focus on displaying the data in a user friendly way. At the same time, we have transitioned the key database components to NCBI. In the medium term, maintaining parallel databases will occur until ClinVar reaches a level of service and sophistication that can replace the BIC database. Over the last year we have also shared the entirety of the BIC database with the BRCA Challenge project sponsored by the Global Alliance for Genomics and Health. This international organization is focused on aiding the dissemination genomics information worldwide. The BRCA Challenge is a demonstration project.. The BRCA Challenge is has to gathered additional BRCA mutation data from several sources and has a stated goal to gather data from parts of the world that do not currently share their data. The BRCA Challenge program recently launched a beta test version of their database call the BRCAExchange (http://brcaexchange.org ) Dr. Brody and others serve on the steering committee for this database. This project does not produce publications. Using out dated metrics for productivity and return on investment will not capture the value of this project. The major fruit of this work is a database and set of analysis tools that are used via direct access. The measured impact of this effort is highly significant. In addition to the usage statistics presented above, the BIC database has been cited by thousands of peer reviewed publications. In terms of other investment of NHGRI into scientific databases, the BIC database remains the most accessed scientific data resource at NHGRI. This rank has held constant for more than two decades. The impact of this investment has only been amplified by the active distribution of these data to others.